Gabapentin

Gabapentin is approved for the treatment of partial-onset seizures in adults and children, and for postherpetic neuralgia, a type of neuropathic pain that persists after shingles. It is also commonly used off-label for diabetic neuropathy, fibromyalgia, and migraine prevention, though evidence for some of these uses is mixed. In addition, gabapentin is prescribed for restless legs syndrome and for managing hot flashes in menopausal women, with some studies showing modest benefit. Its analgesic effects are particularly notable in neuropathic pain, where it is considered a first-line agent alongside pregabalin. However, its efficacy in acute pain is limited, and it is not recommended for routine postoperative pain management.

Gabapentin was designed as a structural analog of GABA, but it does not bind to GABA receptors or affect GABA reuptake or metabolism. Instead, it binds with high affinity to the α2δ-1 subunit of voltage-gated calcium channels, particularly in the central nervous system. This binding reduces calcium influx into presynaptic terminals, thereby decreasing the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P. This modulation is thought to underlie its anticonvulsant and analgesic properties. Gabapentin is absorbed via a saturable transport system, and its bioavailability decreases with increasing doses, leading to nonlinear pharmacokinetics. It is excreted unchanged by the kidneys, and dose adjustment is required in renal impairment.

Common adverse effects include dizziness, somnolence, ataxia, and peripheral edema. These effects are dose-related and often diminish with continued use. Gabapentin can cause serious respiratory depression, especially when combined with opioids or in patients with respiratory risk factors. It may also increase the risk of suicidal thoughts and behavior, as with other antiepileptic drugs. In 2019, the FDA issued a warning about the risk of severe breathing problems in patients using gabapentin or pregabalin. Abrupt discontinuation can precipitate withdrawal symptoms such as anxiety, insomnia, and sweating, so tapering is recommended. Gabapentin is classified as a Schedule V controlled substance in some jurisdictions due to its potential for misuse.

Gabapentin was first synthesized in 1977 by researchers at the pharmaceutical company Goedecke (later part of Pfizer) as an anticonvulsant. It was initially approved in the UK in 1993 and in the US in 1994. A notable off-label use is for the treatment of alcohol withdrawal and alcohol use disorder, with some evidence suggesting it reduces craving and improves sleep. Gabapentin has also been studied for its potential in treating pruritus (itching) of various origins, including uremic pruritus in dialysis patients. In veterinary medicine, it is used to manage chronic pain and anxiety in dogs and cats. Additionally, gabapentin misuse has been increasingly reported, often in combination with opioids, leading to calls for tighter regulation. Its use in pregnancy is not well-studied, but some data suggest a small increased risk of major malformations.

Partial seizures

Seizures that originate in a localized area of the brain, also called focal seizures.

Neuropathic pain

Pain caused by damage or disease affecting the somatosensory nervous system.

α2δ-1 subunit

A protein subunit of voltage-gated calcium channels that is the binding site for gabapentin and pregabalin.

Postherpetic neuralgia

Persistent nerve pain that occurs as a complication of shingles.